G-dimethyosoergolenyl-b



United States Patent O 3,251,846 N-(D-1,6-DIMETHYLISOERGOLENYL-8)-N',N-DIALKYLUREAS Miroslav Semonsky, Viktor Zikn, and Zdenek Votava,Prague, Czechoslovakia, assignors to Spofa, Sdruieni podnikii prozdravotnickou vy'rohu, Prague, Czechoslovalria No Drawing. Filed Sept.5, 1963, Ser. No. 306,671 Claims priority, application Czechoslovakia,

Sept. 5, 1962, 5,128/62 I Claims. (Cl. 260-2855) The invention relatesto new N-(D-1,6-dimethy1isoergolenyl-8)-N',N'-dialkylureas of generalFormula I:

NIELC O.R

wherein R signifies the N(C H or N(CH group, as well as to acid saltsthereof, and to the method of preparing the same.

These new compounds exhibit a significant antiserotonin activity;compared with the corresponding ureas which are not substituted in the N-position, they are less toxic.

The N (D-l,6-dimethylisoergolenyl-8)-N',N'-dialkylureas of the generalFormula I are new compounds not yet reported in the literature, whichwere prepared in the framework of the study in the relations betweenchemical constitution and pharmacological activity.

According to the invention, these compounds are prepared by methylatingthe corresponding N-(D-6-methylisoergolenyl-S)-N,N'-dialkylureas,preferably by means of methyl iodide, in liquid ammonia, and in thepresence of potassium amide. They are isolated by evaporating theammonia, and the crude products are purified by adsorptionchromatography and crystallization.

The ureas obtained by the .method according to the invention, and havingthe general Formula I, form easily crystallizable salts with organic andinorganic acids, e.g. the acid maleate, which are readily soluble inwater. The ureas of the general Formula I, as well as additonalcompounds of this group, exhibit characteristic color reactions, eg theKeller van Urk reactions, which can be used for difierentiating themfrom ureas not substituted at N The difierence is especially significantin the case of the von Urk reaction (the unsubstituted ureas givedeep-blue colour, while the corresponding N methyl derivatives givetobacco-brown colour rapidly turning to a grey-violet color.

The N-(D-6-methylisoergo1enyl-8)-N,N-dialkyl ureas serving as startingmaterial for the preparation of the corresponding N -methyl derivativescan be easily obtained from the D-isolysergic hydrazide via the azideand (D 6 methylisoergolenyl 8)-isocyanate (V. Zikn, M. Semonsky:Collection Czechoslov. Chem. Communs. 25, 1955-1960).

Examples (1) N-(D-1,6-dimethylisoergoleny1-8) N,N diethyl urea.

Ferric nitrate was added to a solution of 270 mg. potassium in 350 m1.anhydrous liquid ammonia, amount of ferric nitrate being just sufiicientjust necessary to decolorize the liquid, and after addition of 2.0 g.finely powdered N-(D-6-methylisoergolenyl-8) N',N diethyl urea themixture was stirred vigorously until the com- 3,251,846 Patented May 17,1966 matography was followed by paper chromatography using formamidewith 5% of ammonium formate as the stationary phase, and a mixture ofbenzene and chloroform as the mobile phase. The elution of the columnwas carried out by means of a mixture of benzene and chloroform (1:2).The combined fractions containing the product were evaporated and theresidue purified by crystallization.

The N-(D-l,6-dimethylisoergolenyl-8) N',N' diethyl urea forms prismsmelting at 120-125 C. (benzene); (oz) =|319 (c=0.5, pyridine); the acidmaleate prisms melting at 165-167 C. (ether-ethanol).

(2) N (D 1,6 dimethylisoergolenyl 8)-N,N-dimethyl urea.

The compound was prepared fi'omN-(D-6-methylisoergolenyl-8)-N,N'-dimethylurea in the same way asdescribed in Example 1. This compound forms prismatic crystals with M.P.-116 C. (acetone); (a) =+335 (c=0.5, pyridine); the acid maleate prismsmelting at 172-173 C. (ethanol).

What we claim is:

1. The compound N (D 1,6-dimethylisoergolenyl-8)- diethyl urea with M.P.-125 C. (a) =i-319 (c=0.5, pyridine), and its acid maleate with M.P. 167C.

2. The compound N-(D-1,6-dimethylisoergolenyl-8)- dimethyl urea withM.P. 115-116 C. (oz) =-]335 (c=0.5, pyridine), and its acid maleate withMP. 172- 173 C.

3. A compound selected from the group consisting of compounds of theformula:

NRC 0.3

wherein R is N(lower alkyl) and non-toxic acid addition salts thereof.

4. N-(D-1,6-dimethylisoergolenyl-8)diethyl urea-acid maleate. 5. N (D1,6-dimethylisoergolenyl-8)dimethyl ureaacid maleate.

References Cited by the Examiner FOREIGN PATENTS 811,964 4/1959 GreatBritain.

OTHER REFERENCES HENRY R. JILES, Acting Primary Examiner. DONALD G.DAUS, Assistant Examiner.

3. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA: